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Importance of Endocytosis for the Biological Activity of Cedar Virus Fusion Protein.

ABSTRACT: Endocytosis plays a particular role in the proteolytic activation of highly pathogenic henipaviruses Hendra (HeV) and Nipah virus (NiV) fusion (F) protein precursors. These proteins require endocytic uptake from the cell surface to be cleaved by cellular proteases within the endosomal compartment, followed by recycling to the plasma membrane for incorporation into budding virions or mediation of cell-cell fusion. This internalization largely depends on a tyrosine-based consensus motif for endocytosis present in the cytoplasmic tail of HeV and NiV F. Given the large number of tyrosine residues present in the F protein cytoplasmic domain of Cedar virus (CedV), a closely related but low pathogenic henipavirus, we aimed to investigate whether CedV F protein undergoes signal-mediated endocytosis from the cell surface controlled by tyrosine-based motifs present in its cytoplasmic tail and whether endocytosis is relevant for its biological activity. Therefore, tyrosine-based signals were mutated, and mutations were assessed for their effect on F cell surface expression, endocytosis, and biological activity. A membrane-proximal YXX? motif and a C-terminal di-tyrosine motif are of particular importance for cell surface expression and endocytosis rate. Furthermore, our data strongly indicate the pivotal role of endocytosis for the biological activity of the CedV F protein.

SUBMITTER: Fischer K

PROVIDER: S-EPMC7565975 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Importance of Endocytosis for the Biological Activity of Cedar Virus Fusion Protein.

Fischer Kerstin K Groschup Martin H MH Diederich Sandra S

Cells 20200908 9

Endocytosis plays a particular role in the proteolytic activation of highly pathogenic henipaviruses Hendra (HeV) and Nipah virus (NiV) fusion (F) protein precursors. These proteins require endocytic uptake from the cell surface to be cleaved by cellular proteases within the endosomal compartment, followed by recycling to the plasma membrane for incorporation into budding virions or mediation of cell-cell fusion. This internalization largely depends on a tyrosine-based consensus motif for endocy ...[more]

PMID: 32911832

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Project description:UnlabelledHuman respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein.ImportanceHuman respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.

Dataset Information

Importance of Endocytosis for the Biological Activity of Cedar Virus Fusion Protein.

Publications

Importance of Endocytosis for the Biological Activity of Cedar Virus Fusion Protein.

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